Chemokine receptor CXCR4 and its cognate ligand CXCL12 have been shown to play important roles in the growth, invasion, and metastasis of breast cancer. Given that metastasis is the major cause of increased morbidity and eventual mortality in breast cancer patients, understanding how signaling molecules modulate the tumor microenvironment that leads to metastasis is of fundamental importance. CXCL12 has been shown to be produced by fibroblasts. Recently, we generated a novel CXCL12 floxed mouse model. Using these mice, we will further analyze the role of stromal CXCL12 in breast cancer progression, angiogenesis, and metastasis. CXCL12 has also been shown to bind to CXCR7. We and others have shown that the CXCL12/CXCR7 pathway plays an important role in enhancing tumor growth and metastasis. In addition, we and others have recently shown that the Slit2/Robo1 pathway possesses tumor suppressive activity through modulation of CXCL12/CXCR4 functional effects. In this proposal, we will further analyze the crosstalk between Slit2/Robo1 and CXCL12/CXCR4/CXCR7 signaling that modulates breast cancer growth, angiogenesis, and metastasis. In addition, we will use an innovative multi-disciplinary approach to analyze the molecular mechanisms by which Slit2/Robo1 inhibits tumor growth and angiogenesis through modulation of the tumor microenvironment. Finally, we will determine the therapeutic potential of Slit2/Robo1 and CXCL12/CXCR4/CXCR7 in breast cancer. Insight gained from these studies will help in developing novel and innovative therapeutic strategies for highly aggressive and metastatic breast cancers, especially triple-negative breast cancer.